Fred W. Sabb, PhD

Neuroimaging research has contributed enormously to our understanding of structural and functional differences between the brains of people with schizophrenia and those of healthy people. Imaging now offers insights into how drugs used to treat schizophrenia work as well as the genetic mechanisms that lie at the root of these disorders.

It has long been acknowledged that the likely pathophysiological and etiological heterogeneity of schizophrenia pose major challenges to research and treatment. While it is clear that schizophrenia has a 10-fold increased risk among first-degree relatives of affected patients, it must also be acknowledged that concordance is only 50% in monozygotic twins.

Thus, we cannot expect that neuroimaging should serve a diagnostic role or guide specific treatment regimens for the phenotype of schizophrenia. Instead, imaging tools may help dissect the contributions of multiple pathophysiological processes that increase vulnerability and identify patterns of impaired and preserved neural system function. We attempt to summarize key challenges and promising leads from current research.

Structural neuroimaging in schizophrenia gained major ground with the advent of CT scanning in the 1980s. Widespread availability of MRI in the 1990s revolutionized our ability to obtain detailed images of anatomic structure without risks of ionizing radiation. These methods have now revealed a plethora of findings that statistically differentiate people with schizophrenia from unaffected individuals, but no single abnormality has emerged as the necessary and sufficient substrate of the syndrome. Most individual anomalies show substantial overlap between the patient and healthy distributions of values.

Well-replicated findings show enlargements of the ventricular system and subarachnoid cerebrospinal fluid (CSF) spaces and decreases in the volumes of most cortical gray matter regions. The most attention has been given to regions in the frontal lobe, temporal lobe, hippocampal formation, cingulate gyrus, thalamus, and cerebellum.

 Some investigators have suggested critical deficits in localized regions of interest, such as the superior temporal gyrus.

However, most current hypotheses focus on likely disturbances of broader systems of interconnected regions (e.g., frontolimbic and frontostriatal systems)

 or deficits affecting cortical gray matter either in a widespread fashion

 or within somewhat more circumscribed cytoarchitectonic territories (such as the heteromodal association cortices).

There also are suggestions that the normal asymmetries of the brain may be absent in schizophrenia.

 While initial studies of structural anomalies in the brain tended to focus on measuring the volumes of specific regions of interest, innovations in image analysis (including voxel-based morphometry and continuum mechanical tensor mapping) now permit mapping of structural variation across the entire brain or over the entire surface of structures such as the hippocampal formation. These studies show the pattern of cortical gray matter thickness deficit across the entire brain. Maximal hippocampal volume reductions are observed in the lateral mid-to-anterior regions of this structure, which implicates specific neural systems linking hippocampal and cortical regions

One study used automated image analysis methods to identify a combination of abnormalities that enabled a high level of discrimination between schizophrenic and healthy groups (the overall classification accuracy was 81%).

 While such methods are not yet useful diagnostically, future diagnosis and treatment may benefit from rapid characterization of similar subtle features.

Given hypotheses that schizophrenia may be characterized by a failure of communication among important brain regions, one relatively new technique, diffusion tensor imaging, has received considerable attention. It examines the patterns of water diffusion in tissue. If water is unconstrained, it diffuses randomly in all directions (i.e., isotropic). When diffusion is constrained by cellular structure (as occurs in white matter tracts), the water flow is more directional (anisotropic).

While some studies have shown decreased anisotropy consistent with white matter abnormalities, a review highlights inconsistent results and suggests that this emerging field will benefit from improved reproducibility as the methodology becomes better standardized.

It was once thought unlikely that drugs used to treat schizophrenia would affect neuroanatomy on a level that could be seen in vivo, but it is now accepted that treatment can influence the overall volume of brain structures visible with neuroimaging. Chakos and colleagues showed increased caudate volume with conventional neuroleptic treatment, which was reversed by subsequent clozapine (Clozaril) treatment, findings attributed to the relative potency of these drugs' actions at D2 dopamine receptors.

 More recent work also suggests that other antipsychotic agents may be associated with volume changes in neocortical regions, although the mechanisms underlying this relationship remain unclear.

Early CT studies hypothesized that patterns of structural brain abnormality might be used to predict treatment response or outcome. Some research supports the general idea that patients with more severe structural pathology are less likely to respond well to treatments. However, application of structural imaging tools to enable more definitive treatment or prognostication remains elusive. Current practice employs imaging principally to rule out other neurological disorders, with some suggestions that high-resolution MRI should be a practice standard in the diagnostic workup of first-episode patients.

Functional imaging is one of the hottest growth areas in neuroscience, promoted largely by the increasing availability of MRI equipment that can measure blood oxygen level-dependent signal (BOLD).

Initial reports using PET to study cerebral glucose metabolism or blood flow showed reduced activity in the frontal lobes either at rest or while patients attempted cognitive tasks. Other functional MRI studies support this concept.

 A meta-analysis suggests this is the most robust neuroimaging finding distinguishing schizophrenia.

Another meta-analysis of fMRI studies that used a specific working memory paradigm concluded that the pattern of activation abnormalities (including both decreases and increases) across complex networks including frontal lobe and other linked regions is more informative.

 Complicating these interpretations, some studies show underactivation, while others show overactivation in response to cognitive challenges. The latter findings are often interpreted as revealing inefficiency of the neural systems involved.

Future activation imaging studies will likely employ more sophisticated designs to characterize the dynamic response of frontal lobe and related regions to challenges of varying complexity. This will effectively offer a graded stress test to see how these systems respond to changing demands.

Exciting new research combines activation imaging with pharmacological manipulations and/or genetic information. For example, Honey and colleagues showed normalization of frontoparietal fMRI activation in response to a working memory challenge. Patients with schizophrenia were switched from conventional antipsychotics to risperidone (Risperdal)

Several studies have now shown effects of genetic polymorphisms on the patterns of activation elicited by cognitive challenges and even complex four-way interactions among diagnosis, cognitive challenge condition, genotype, and pharmacological manipulation. For example, a polymorphism in the gene coding for the enzyme catechol-O-methyltransferase (COMT) has a significant effect on the breakdown of dopamine. Patients with schizophrenia who have the form of this gene linked to lower prefrontal dopamine showed greater inefficiency of prefrontal activation response to cognitive challenge and also altered change in this response when given amphetamine.

Another report examined the gene DISC1 (disrupted in schizophrenia), which was previously associated with a higher incidence of psychopathology in a family study.

 Overtransmission of a certain polymorphism (Ser704Cys) was associated with reduced gray matter volume as well as deficits in performance and activation in fMRI experiments. While these methods are not ready for clinical application, future imaging studies will characterize patients by their responses to specific cognitive and pharmacological challenges, considering the genetic variations that affect these responses.

While many current hypotheses about the mechanisms of antipsychotic agents are linked to receptor binding profiles observed in vitro, neuroimaging has been instrumental in advancing knowledge of receptor modulation in vivo. Early versions of the dopamine hypothesis (i.e., that excessive transmission of dopamine exists) were based on the observation that effective antipsychotic agents block dopamine D2 receptors. Molecular imaging studies using specific ligands to map dopamine receptor binding and other indices of dopamine metabolism show that the situation is not so simple.

In an excellent review of this literature, Abi-Dargham and Laruelle concluded that the evidence supports a complex pattern of excessive D2 stimulation subcortically and decreased transmission (at D1 receptors) cortically, and suggested that this may be consistent with a primary abnormality in N-methyl-D-aspartate transmission.

 Comparisons of first- and second-generation antipsychotics show that reduced extrapyramidal side effects (EPS) can be explained by lower D2 occupancy. However, it is possible that the 5-HT2a binding of some novel antipsychotic agents, together with D2 blockade, indirectly increases D1 transmission cortically and thereby has beneficial effects. Some PET studies also have examined the therapeutic window for D2 occupancy. There is some consensus that a D2 occupancy of approximately 50% may be necessary to achieve therapeutic efficacy for positive symptoms, while an occupancy greater than 80% may produce EPS23 (Figure 3).

While the current expense of PET may rule out its widespread clinical use, this knowledge already has affected research and prescribing practices, so that lower doses of D2-blocking agents are often used. As new ligands are developed and our understanding of the neuropsychopharmacology of complex frontolimbic and striatal systems matures, there is hope that future prescriptions and dose titration will be decided based on receptor occupancy and pharmacodynamic responses.

Structural imaging has provided important clues about a multiplicity of pathophysiological processes that may underlie schizophrenia and helped the field appreciate the likely neurodevelopmental roots of this complex syndrome. Future work can be expected to clarify the onset and developmental trajectory of these abnormalities by studying individuals at risk for psychosis by virtue of heredity or behavior and perhaps foster clearer subtyping and better prognostication.

Functional and molecular imaging tools are rapidly changing our concepts of treatment, both at the level of receptor binding and more complex neural systems engagement during cognitive stress tests. While these breakthroughs may remain on the horizon, we remain optimistic that realizing this vision is not a matter of if but when.

Dr. Sabb is a neuroscientist and postdoctoral fellow at the University of California, Los Angeles. Dr. Bilder is a professor of psychiatry and biobehavioral sciences at the David Geffen School of Medicine and chief of medical psychology-neuropsychology at the Semel Institute for Neuroscience & Human Behavior at UCLA.

Note: A version of this article appeared in our sister publication Psychiatric Times. It has been revised for DI Europe.

 Davidson LL, Heinrichs RW. Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis. Psychiatry Res 2003;122(2):69-87.


 McCarley RW, Niznikiewicz MA, Salisbury DF, et al. Cognitive dysfunction in schizophrenia: unifying basic research and clinical aspects. Eur Arch Psychiatry Clin Neurosci 1999;249(suppl 4):69-82.


 Shenton ME, Dickey CC, Frumin M, et al. A review of MRI findings in schizophrenia. Schizophr Res 2001;49(1-2):1-52.


 Lencz T, Cornblatt B, Bilder RM. Neurodevelopmental models of schizophrenia: pathophysiologic synthesis and directions for intervention research. Psychopharmacol Bull 2001;35(1):95-125.


 Meyer-Lindenberg A, Miletich RS, Kohn PD, et al. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002;5(3):267-271.


 Pfefferbaum A, Marsh L. Structural brain imaging in schizophrenia. Clin Neurosci 2005;3(2):105-111.


 Pfefferbaum A, Lim KO, Rosenbloom M, et al. Brain magnetic resonance imaging: approaches for investigating schizophrenia. Schizophr Bull 1990;16(3):453-476.


 Pearlson GD. Superior temporal gyrus and planum temporale in schizophrenia: a selective review. Prog Neuropsychopharmacol Biol Psychiatry 1997;21(8):1203-1229.


 Bilder RM, Wu H, Chakos MH, et al. Cerebral morphometry and clozapine treatment in schizophrenia. J Clin Psychiatry 1994;55(suppl B):53-56.


 Narr KL, Bilder RM, Toga AW, et al. Mapping cortical thickness and gray matter concentration in first episode schizophrenia. Cereb Cortex 2005;15(6):708-719.


 Narr KL, Thompson PM, Szeszko P, et al. Regional specificity of hippocampal volume reductions in first-episode schizophrenia. Neuroimage 2004;21(4):1563-1575.


 Davatzikos C, Shen D, Gur RC, et al. Whole-brain morphometric study of schizophrenia revealing a spatially complex set of focal abnormalities. Arch Gen Psychiatry 2005;2(11):1218-1227.


 Kanaan RA, Kim JS, Kaufmann WE, et al. Diffusion tensor imaging in schizophrenia. Biol Psychiatry 2005 [epub ahead of print].


 Chakos MH, Lieberman JA, Bilder RM, et al. Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am J Psychiatry 1994;151(10):1430-1436.


 Hoptman MJ, Volavka J, Weiss EM, et al. Quantitative MRI measures of orbitofrontal cortex in patients with chronic schizophrenia or schizoaffective disorder. Psychiatry Res 2005;140(2):133-145.


 Lieberman JA, Tollefson GD, Charles C, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005;62(4):361-370.


 Winterer G, Weinberger DR . Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 2004;27(11):683-690.


 Glahn DC, Ragland JD, Abramoff A. Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp 2005;25(1):60-69.


 Honey GD, Bullmore ET, Soni W. Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci USA1999;96(23):13432-13437.


 Mattay VS, Goldberg TE, Fera F, et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 2003;100(10):6186-6191.


 Callicott JH, Straub RE, Pezawas L, et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005;102(24):8627-8632.


 Abi-Dargham A, Laruelle M. Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies. Eur Psychiatry 2005;20(1):15-27.


 Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 2003;27(7):1081-1090.


 Cannon C. Clinical and genetic high-risk strategies in understanding vulnerability to psychosis. Schizophr Res 2005;79(1):35-44.

Articles

Multiple modalities explore schizophrenia

Structural neuroimaging in schizophrenia gained major ground with the advent of CT scanning in the 1980s. Widespread availability of MRI in the 1990s revolutionized our ability to obtain detailed images of anatomic structure without risks of ionizing radiation. These methods have now revealed a plethora of findings that statistically differentiate people with schizophrenia from unaffected individuals, but no single abnormality has emerged as the necessary and sufficient substrate of the syndrome. Most individual anomalies show substantial overlap between the patient and healthy distributions of values.1

Well-replicated findings show enlargements of the ventricular system and subarachnoid cerebrospinal fluid (CSF) spaces and decreases in the volumes of most cortical gray matter regions. The most attention has been given to regions in the frontal lobe, temporal lobe, hippocampal formation, cingulate gyrus, thalamus, and cerebellum.1 Some investigators have suggested critical deficits in localized regions of interest, such as the superior temporal gyrus.2,3

However, most current hypotheses focus on likely disturbances of broader systems of interconnected regions (e.g., frontolimbic and frontostriatal systems)4,5 or deficits affecting cortical gray matter either in a widespread fashion6,7 or within somewhat more circumscribed cytoarchitectonic territories (such as the heteromodal association cortices).8

There also are suggestions that the normal asymmetries of the brain may be absent in schizophrenia.9 While initial studies of structural anomalies in the brain tended to focus on measuring the volumes of specific regions of interest, innovations in image analysis (including voxel-based morphometry and continuum mechanical tensor mapping) now permit mapping of structural variation across the entire brain or over the entire surface of structures such as the hippocampal formation. These studies show the pattern of cortical gray matter thickness deficit across the entire brain. Maximal hippocampal volume reductions are observed in the lateral mid-to-anterior regions of this structure, which implicates specific neural systems linking hippocampal and cortical regions10,11 (Figure 1).

One study used automated image analysis methods to identify a combination of abnormalities that enabled a high level of discrimination between schizophrenic and healthy groups (the overall classification accuracy was 81%).12 While such methods are not yet useful diagnostically, future diagnosis and treatment may benefit from rapid characterization of similar subtle features.

While some studies have shown decreased anisotropy consistent with white matter abnormalities, a review highlights inconsistent results and suggests that this emerging field will benefit from improved reproducibility as the methodology becomes better standardized.13

It was once thought unlikely that drugs used to treat schizophrenia would affect neuroanatomy on a level that could be seen in vivo, but it is now accepted that treatment can influence the overall volume of brain structures visible with neuroimaging. Chakos and colleagues showed increased caudate volume with conventional neuroleptic treatment, which was reversed by subsequent clozapine (Clozaril) treatment, findings attributed to the relative potency of these drugs' actions at D2 dopamine receptors.14 More recent work also suggests that other antipsychotic agents may be associated with volume changes in neocortical regions, although the mechanisms underlying this relationship remain unclear.15,16

Functional imaging is one of the hottest growth areas in neuroscience, promoted largely by the increasing availability of MRI equipment that can measure blood oxygen level-dependent signal (fMRI).

Initial reports using PET to study cerebral glucose metabolism or blood flow showed reduced activity in the frontal lobes either at rest or while patients attempted cognitive tasks. Other fMRI studies support this concept.17 A meta-analysis suggests this is the most robust neuroimaging finding distinguishing schizophrenia.1

Another meta-analysis of fMRI studies that used a specific working memory paradigm concluded that the pattern of activation abnormalities (including both decreases and increases) across complex networks including frontal lobe and other linked regions is more informative.18 Complicating these interpretations, some studies show underactivation, while others show overactivation in response to cognitive challenges. The latter findings are often interpreted as revealing inefficiency of the neural systems involved.17

Exciting new research combines activation imaging with pharmacological manipulations and/or genetic information. For example, Honey and colleagues showed normalization of frontoparietal fMRI activation in response to a working memory challenge. Patients with schizophrenia were switched from conventional antipsychotics to risperidone (Risperdal)19 (Figure 2).

Several studies have now shown effects of genetic polymorphisms on the patterns of activation elicited by cognitive challenges and even complex four-way interactions between diagnosis, cognitive challenge condition, genotype, and pharmacological manipulation. For example, a polymorphism in the gene coding for the enzyme catechol-O-methyltransferase (COMT) has a significant effect on the breakdown of dopamine. Patients with schizophrenia who have the form of this gene linked to lower prefrontal dopamine showed greater inefficiency of prefrontal activation response to cognitive challenge and also altered change in this response when given amphetamine.20

Another report examined the gene DISC1 (disrupted in schizophrenia), which was previously associated with a higher incidence of psychopathology in a family study.21 Overtransmission of a certain polymorphism (Ser704Cys) was associated with reduced gray matter volume as well as deficits in performance and activation in fMRI experiments. While these methods are not ready for clinical application, future imaging studies will characterize patients by their responses to specific cognitive and pharmacological challenges, considering the genetic variations that affect these responses.

In an excellent review of this literature, Abi-Dargham and Laruelle concluded that the evidence supports a complex pattern of excessive D2 stimulation subcortically and decreased transmission (at D1 receptors) cortically, and suggested that this may be consistent with a primary abnormality in N-methyl-D-aspartate transmission.22 Comparisons of first- and second-generation antipsychotics show that reduced extrapyramidal side effects (EPS) can be explained by lower D2 occupancy. However, it is possible that the 5-HT2a binding of some novel antipsychotic agents, together with D2 blockade, indirectly increases D1 transmission cortically and thereby has beneficial effects. Some PET studies also have examined the therapeutic window for D2 occupancy. There is some consensus that a D2 occupancy of approximately 50% may be necessary to achieve therapeutic efficacy for positive symptoms, while an occupancy greater than 80% may produce EPS23 (Figure 3).

Structural imaging has provided important clues about a multiplicity of pathophysiological processes that may underlie schizophrenia and helped the field appreciate the likely neurodevelopmental roots of this complex syndrome. Future work can be expected to clarify the onset and developmental trajectory of these abnormalities by studying individuals at risk for psychosis by virtue of heredity or behavior and perhaps foster clearer subtyping and better prognostication.24

Note: A version of this article appeared in the February issue of Psychiatric Times. It has been revised for Diagnostic Imaging.

1. Davidson LL, Heinrichs RW. Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis. Psychiatry Res 2003;122(2):69-87.

2. McCarley RW, Niznikiewicz MA, Salisbury DF, et al. Cognitive dysfunction in schizophrenia: unifying basic research and clinical aspects. Eur Arch Psychiatry Clin Neurosci 1999;249(suppl 4):69-82.

3. Shenton ME, Dickey CC, Frumin M, et al. A review of MRI findings in schizophrenia. Schizophr Res 2001;49(1-2):1-52.

4. Lencz T, Cornblatt B, Bilder RM. Neurodevelopmental models of schizophrenia: pathophysiologic synthesis and directions for intervention research. Psychopharmacol Bull 2001;35(1):95-125.

5. Meyer-Lindenberg A, Miletich RS, Kohn PD, et al. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002;5(3):267-271.

6. Pfefferbaum A, Marsh L. Structural brain imaging in schizophrenia. Clin Neurosci 2005;3(2):105-111.

7. Pfefferbaum A, Lim KO, Rosenbloom M, et al. Brain magnetic resonance imaging: approaches for investigating schizophrenia. Schizophr Bull 1990;16(3):453-476.

8. Pearlson GD. Superior temporal gyrus and planum temporale in schizophrenia: a selective review. Prog Neuropsychopharmacol Biol Psychiatry 1997;21(8):1203-1229.

9. Bilder RM, Wu H, Chakos MH, et al. Cerebral morphometry and clozapine treatment in schizophrenia. J Clin Psychiatry 1994;55(suppl B):53-56.

10. Narr KL, Bilder RM, Toga AW, et al. Mapping cortical thickness and gray matter concentration in first episode schizophrenia. Cereb Cortex 2005;15(6):708-719.

11. Narr KL, Thompson PM, Szeszko P, et al. Regional specificity of hippocampal volume reductions in first-episode schizophrenia. Neuroimage 2004;21(4):1563-1575.

12. Davatzikos C, Shen D, Gur RC, et al. Whole-brain morphometric study of schizophrenia revealing a spatially complex set of focal abnormalities. Arch Gen Psychiatry 2005;2(11):1218-1227.

13. Kanaan RA, Kim JS, Kaufmann WE, et al. Diffusion tensor imaging in schizophrenia. Biol Psychiatry 2005 [epub ahead of print].

14. Chakos MH, Lieberman JA, Bilder RM, et al. Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am J Psychiatry 1994;151(10):1430-1436.

15. Hoptman MJ, Volavka J, Weiss EM, et al. Quantitative MRI measures of orbitofrontal cortex in patients with chronic schizophrenia or schizoaffective disorder. Psychiatry Res 2005;140(2):133-145.

16. Lieberman JA, Tollefson GD, Charles C, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005;62(4):361-370.

17. Winterer G, Weinberger DR . Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 2004;27(11):683-690.

18. Glahn DC, Ragland JD, Abramoff A. Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp 2005;25(1):60-69.

19. Honey GD, Bullmore ET, Soni W. Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci USA1999;96(23):13432-13437.

20. Mattay VS, Goldberg TE, Fera F, et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 2003;100(10):6186-6191.

21. Callicott JH, Straub RE, Pezawas L, et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005;102(24):8627-8632.

22. Abi-Dargham A, Laruelle M. Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies. Eur Psychiatry 2005;20(1):15-27.

23. Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 2003;27(7):1081-1090.

24. Cannon C. Clinical and genetic high-risk strategies in understanding vulnerability to psychosis. Schizophr Res 2005;79(1):35-44.

Imaging may not diagnose actual condition, but it gives researchers insight into drug and genetic mechanisms

Fred W. Sabb, PhD

Articles

Multiple modalities explore schizophrenia

Multiple modalities explore roots of schizophrenia